Solving opioid receptor structures
RESEARCH HIGHLIGHT
08 February 2023
The G protein-coupled opioid receptors (ORs) — comprising the μ, δ, κ and nociceptin receptor (MOR, DOR, KOR and NOPR) — are widely distributed in the central and peripheral nervous system, where they are activated by endogenous opioid peptides (EOPs) to execute various physiological effects including intrinsic analgesia. Opioid drugs targeting the MOR mimic the analgesic functions of EOPs, but their use is heavily restricted by the severe side effects of respiratory depression and addiction. Hampering the design of safer analgesics is a lack of structural understanding of how EOPs recognize and activate their respective ORs. Here, Wang et al. report the cryogenic electron microscopy structures of OR-Gi signalling complexes activated by opioid peptides, including four EOPs, β-endorphin, endomorphin, dynorphin and nociceptin, and the exogenous opioid peptide deltorphin. These structures reveal a universal activation mechanism for all four opioid ORs — all opioid peptides occupy a highly conserved activation chamber at the bottom of the orthosteric binding pocket of ORs, which is engaged by the N-terminal opioid peptide motif, YGGF — and identify unique structural features within the extracellular loops ECL2 and ECL3 mediating receptor selectivity.
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doi: https://doi.org/10.1038/d41573-023-00022-y
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